Ritonavir-Enhanced Pharmacokinetics of Nelfinavir/M8 during Rifampin Use

2003 ◽  
Vol 37 (4) ◽  
pp. 521-525 ◽  
Author(s):  
Alina S Bergshoeff ◽  
Tom FW Wolfs ◽  
Sibyl PM Geelen ◽  
David M Burger
Keyword(s):  
Steady State ◽  
Protease Inhibitor ◽  
Highly Active Antiretroviral Therapy ◽  
Adult Population ◽  
Plasma Concentrations ◽  
Pharmacokinetic Interaction ◽  
Male Infant ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Highly Active

OBJECTIVE: To describe a case of successful protease inhibitor–based highly active antiretroviral therapy (HAART) concomitant with rifampin. CASE SUMMARY: In a 7-month-old male infant with tuberculosis and HIV-1 infection, tuberculosis therapy including rifampin and HAART containing the protease inhibitor nelfinavir 40 mg/kg every 8 hours was started. Intensive steady-state pharmacokinetic sampling from baseline to 8 hours revealed very low plasma concentrations of nelfinavir: area under the plasma concentration–time curve (AUC0–24) <10% of adult population values for 750 mg every 8 hours and nonquantifiable concentrations of nelfinavir's principal metabolite (M8). Nelfinavir 40 mg/kg every 8 hours was then substituted with nelfinavir 30 mg/kg twice daily plus ritonavir 400 mg/m2 twice daily. Intensive steady-state (0–12 h) pharmacokinetic sampling was repeated. Nelfinavir concentrations had improved, but remained low when compared with adult population values of 1250 mg every 12 hours: AUC0–24 21.9 versus 47.6 mg/L•h (46%) and 12-hour trough level (C12) 0.25 versus 0.85 mg/L (29%). However, concentrations of M8 considerably exceeded population values: AUC0–24 57.5 versus 13.6 mg/L•h (443%) and C12 1.35 versus 0.28 mg/L (482%). Since M8 concentrations were highly elevated, pharmacokinetic parameters for (nelfinavir + M8) were used rather than those for nelfinavir alone. Thus, AUC0–24 (nelfinavir + M8) and C12 (nelfinavir + M8) comprised 130% and 142%, respectively of the adult population values. This, in addition to good clinical response and tolerability, favored continuation of the regimen. CONCLUSIONS: In an infant, nelfinavir-containing HAART was successfully used with rifampin after the addition of ritonavir. Ritonavir resolved the pharmacokinetic interaction between rifampin and nelfinavir by boosting nelfinavir and, especially, M8 concentrations. More research is needed to confirm these results.

scholarly journals Pharmacokinetics of Saquinavir, Atazanavir, and Ritonavir in a Twice-Daily Boosted Double-Protease Inhibitor Regimen

2007 ◽  
Vol 51 (4) ◽  
pp. 1431-1439 ◽  
Author(s):  
Nils von Hentig ◽  
Axel Müller ◽  
Carsten Rottmann ◽  
Timo Wolf ◽  
Thomas Lutz ◽  
...  
Keyword(s):  
Steady State ◽  
Protease Inhibitor ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Life Time ◽  
Time Curve ◽  
Once Daily ◽  
Therapy Regimen ◽  
Drug Concentrations ◽  
Group 2

ABSTRACT The objective of this study was to evaluate the pharmacokinetics of atazanavir (ATV), saquinavir (SQV), and ritonavir (RTV) in a boosted double-protease inhibitor (PI) therapy regimen without reverse transcriptase inhibitors (RTIs). The study design was as follows. Patients with limited RTI options received a PI combination of 300/100 mg ATV/RTV once daily and 1,000 mg SQV twice daily (group 1; n = 49) without RTI comedication. The results were compared to the plasma concentrations of PIs of patients taking either 300 mg ATV/100 mg RTV once daily plus RTIs (group 2; n = 72) or patients taking 1,000 mg SQV/100 mg RTV plus RTIs (group 3; n = 90). The study methods were as follows. Patients were given a 12/24-h pharmacokinetic assessment at steady state. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry. The minimum and maximum concentrations (C min and C max), area under the concentration-time curve under steady-state conditions (AUCss), elimination half-life, time of maximum concentration and lag time were subject to statistical analysis. The results show that patients treated with ATV/SQV/RTV exhibited significantly high SQV concentrations and moderate enhancement of the AUCss of ATV in comparison to those of patients of the control groups: for SQV in groups 1 and 3, the geometric mean (GM) of the AUCss was 22,794 versus 15,759 ng·h/ml (GM ratio [GMR] = 1.45; P < 0.05), the GM of the C max was 3,257 versus 2,331 ng/ml (GMR = 1.40; P < 0.05), and the GM of the C min was 438 versus 437 ng/ml (GMR = 1.00); for ATV in groups 1 and 2, the GM of the AUCss was 39,154 versus 33,626 ng·h/ml (GMR = 1.16), the GM of the C max was 3,488 versus 2,924 ng/ml (GMR = 1.20), and the GM of the C min was 515 versus 428 ng/ml (GMR = 1.21). RTV levels were comparable for all groups. A subgroup analysis detected only marginal differences in ATV plasma exposure if combined with tenofovir-disoproxilfumarate and without it. We conclude that our pharmacokinetic results support the use of a boosted double-PI regimen of ATV/SQV/RTV as a treatment option for patients who need antiretroviral therapy without RTIs.

scholarly journals Lack of Pharmacokinetic Interaction between Linezolid and Antacid in Healthy Volunteers

2006 ◽  
Vol 50 (1) ◽  
pp. 68-72 ◽  
Author(s):  
Gabriela Grunder ◽  
Yvonne Zysset-Aschmann ◽  
Florence Vollenweider ◽  
Thomas Maier ◽  
Stephan Krähenbühl ◽  
...  
Keyword(s):  
Aluminum Hydroxide ◽  
Magnesium Hydroxide ◽  
Oral Absorption ◽  
Randomized Study ◽  
Plasma Concentrations ◽  
Pharmacokinetic Interaction ◽  
Pharmacokinetic Parameters ◽  
Individual Values ◽  
Time Curve ◽  
Significant Difference

ABSTRACT Several antibiotics show significant pharmacokinetic interactions when they are given orally concomitantly with antacids. The objective of this study was to evaluate the effects of antacid (containing magnesium) on the pharmacokinetics of linezolid. A single dose of 600 mg linezolid was given orally alone and 10 min after administration of the antacid Maalox 70mVal, which contains 600 mg magnesium hydroxide and 900 mg aluminum hydroxide, to nine healthy males and nine healthy females in a crossover and randomized study. Linezolid plasma concentrations were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated for both treatments. Coadministration with antacids did not change the pharmacokinetics of linezolid. The ratios (90% confidence intervals) of the individual values of the area under the concentration-time curve and the maximum concentration in plasma (C max) (linezolid plus antacid versus linezolid alone) were 1.01 (0.99 to 1.02) and 0.99 (0.96 to 1.02), respectively. Likewise, no significant difference in any of the other pharmacokinetic parameters was observed between the treatment groups (the time to C max, lag time, volume of distribution [V/F], and clearance [CL/F]). However, a significant sex difference was observed for AUC, C max, V/F, and CL/F; and these differences could be almost completely explained by the differences in body weight between males and females. No clinically relevant adverse effects were detected under either condition. The coadministration of antacids had no effect on the pharmacokinetics of linezolid. This demonstrates that the oral absorption of linezolid was not affected by the presence of antacids containing magnesium hydroxide and aluminum hydroxide. Antacids can be safely administered together with linezolid.

Protease inhibitor drug levels in the management of human immunodeficiency virus-1 antiretrovial therapy

2003 ◽  
Vol 14 (2) ◽  
pp. 103-108 ◽  
Author(s):  
A W Urban ◽  
P Bean ◽  
D Aziz ◽  
F M Graziano ◽  
B L Neudeck
Keyword(s):  
Protease Inhibitor ◽  
Highly Active Antiretroviral Therapy ◽  
Plasma Concentrations ◽  
Drug Level ◽  
Outpatient Setting ◽  
Hiv Rna ◽  
Highly Active ◽  
Group 2 ◽  
Inhibitor Drug ◽  
Group 1

In order to evaluate the relationship between protease inhibitor (PI) plasma concentrations and viral suppression in individuals receiving highly active antiretroviral therapy (HAART), plasma concentrations and area under the time concentration curve (AUC0.5–4) for 35 HIV-infected adults receiving their initial (or first salvage) nelfinavir- (NFV) or indinavir (IDV)-based HAART were studied. Two groups were evaluated: those who had achieved HIV-RNA suppression (HIV-RNA <500 copies/mL, group 1, n=21) and those who had achieved incomplete HIV-RNA suppression (HIV-RNA>500 copies/mL, group 2, n=14) at the time of study entry. NFV one-hour pre-dose concentrations were significantly higher in group 1 compared to group 2 ( P=0.023). The NFV AUC0.5–4 for group 1 approached significance ( P=0.068). No significant differences in IDV concentrations or AUC0.5–4 were found between group 1 and group 2. It is feasible to use PI drug level monitoring in the outpatient setting.

scholarly journals Effect of Pregnancy on the Pharmacokinetic Interaction between Efavirenz and Lumefantrine in HIV-Malaria Coinfection

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Adebanjo Adegbola ◽  
Rana Abutaima ◽  
Adeniyi Olagunju ◽  
Omotade Ijarotimi ◽  
Marco Siccardi ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Pregnant Women ◽  
Plasma Concentrations ◽  
Pharmacokinetic Interaction ◽  
Malaria Treatment ◽  
Interquartile Range ◽  
Pharmacokinetic Parameters ◽  
Standard Regimen ◽  
Time Curve ◽  
A Prospective Study

ABSTRACT Artemether-lumefantrine is often coadministered with efavirenz-based antiretroviral therapy for malaria treatment in HIV-infected women during pregnancy. Previous studies showed changes in lumefantrine pharmacokinetics due to interaction with efavirenz in nonpregnant adults. The influence of pregnancy on this interaction has not been reported. This pharmacokinetic study involved 35 pregnant and 34 nonpregnant HIV-malaria-coinfected women receiving efavirenz-based antiretroviral therapy and was conducted in four health facilities in Nigeria. Participants received a 3-day standard regimen of artemether-lumefantrine for malaria treatment, and intensive pharmacokinetic sampling was conducted from 0.5 to 96 h after the last dose. Plasma efavirenz, lumefantrine, and desbutyl-lumefantrine were quantified using validated assays, and pharmacokinetic parameters were derived using noncompartmental analysis. The median middose plasma concentrations of efavirenz were significantly lower in pregnant women (n = 32) than in nonpregnant women (n = 32) at 1,820 ng/ml (interquartile range, 1,300 to 2,610 ng/ml) versus 2,760 ng/ml (interquartile range, 2,020 to 5,640 ng/ml), respectively (P = 0.006). The lumefantrine area under the concentration-time curve from 0 to 96 h was significantly higher in pregnant women (n = 27) at 155,832 ng · h/ml (interquartile range, 102,400 to 214,011 ng · h/ml) than nonpregnant women at 90,594 ng · h/ml (interquartile range, 58,869 to 149,775 ng · h/ml) (P = 0.03). A similar trend was observed for the lumefantrine concentration at 12 h after the last dose of lumefantrine, which was 2,870 ng/ml (interquartile range, 2,180 to 4,880 ng/ml) versus 2,080 ng/ml (interquartile range, 1,190 to 2,970 ng/ml) in pregnant and nonpregnant women, respectively (P = 0.02). The lumefantrine-to-desbutyl-lumefantrine ratio also tended to be lower in pregnant women than in nonpregnant women (P = 0.076). Overall, pregnancy tempered the extent of efavirenz-lumefantrine interactions, resulting in increased lumefantrine exposure. However, any consideration of dosage adjustment for artemether-lumefantrine to enhance exposure in this population needs to be based on data from a prospective study with safety and efficacy endpoints.

scholarly journals Pharmacokinetic Interaction between Fosamprenavir-Ritonavir and Rifabutin in Healthy Subjects

2007 ◽  
Vol 52 (2) ◽  
pp. 534-538 ◽  
Author(s):  
Susan L. Ford ◽  
Ya-Chi Chen ◽  
Yu Lou ◽  
Julie Borland ◽  
Sherene S. Min ◽  
...  
Keyword(s):  
Steady State ◽  
Systemic Exposure ◽  
Pharmacokinetic Interaction ◽  
Concomitant Administration ◽  
Pharmacokinetic Parameters ◽  
Phosphate Ester ◽  
Open Label ◽  
Time Curve ◽  
Dosing Interval ◽  
Cyp3a4 Inhibitors

ABSTRACT Rifabutin (RFB) is administered for treatment of tuberculosis and Mycobacterium avium complex infection, including use for patients coinfected with human immunodeficiency virus (HIV). Increased systemic exposure to RFB and its equipotent active metabolite, 25-O-desacetyl-RFB (dAc-RFB), has been reported during concomitant administration of CYP3A4 inhibitors, including ritonavir (RTV), lopinavir, and amprenavir (APV); therefore, a reduction in the RFB dosage is recommended when it is coadministered with these protease inhibitors. Fosamprenavir (FPV), the phosphate ester prodrug of the HIV type 1 protease inhibitor APV, is administered either with or without RTV. A randomized, open-label, two-period, two-sequence, balanced, crossover drug interaction study was conducted with 22 healthy adult subjects to compare steady-state plasma RFB pharmacokinetic parameters during concomitant administration of FPV-RTV (700/100 mg twice a day [BID]) with a 75%-reduced RFB dose (150 mg every other day [QOD]) to the standard RFB regimen (300 mg once per day [QD]) by geometric least-squares mean ratios. Relative to results with RFB (300 mg QD), coadministration of dose-adjusted RFB with FPV-RTV resulted in an unchanged RFB area under the concentration-time curve for 0 to 48 h (AUC0-48) and a 14% decrease in the maximum concentration of drug in plasma (C max), whereas the AUC0-48 and C max of dAc-RFB were increased by 11- and 6-fold, respectively, resulting in a 64% increase in the total antimycobacterial AUC0-48. Relative to historical controls, the plasma APV AUC from 0 h to the end of the dosing interval (AUC0-τ) and C max were increased ∼35%, and the concentration at the end of the dosing interval at steady state was unchanged following coadministration of RFB with FPV-RTV. The safety profile of the combination of RFB and FPV-RTV was consistent with previously described events with RFB or FPV-RTV alone. Based on the results of this study, a reduction in the RFB dose by ≥75% (to 150 mg QOD or three times per week) is recommended when it is coadministered with FPV-RTV (700/100 mg BID).

scholarly journals A Pilot Study of Immune Activation and Rifampin Absorption in HIV-Infected Patients without Tuberculosis Infection: A Short Report

2017 ◽  
Vol 2017 ◽  
pp. 1-7
Author(s):  
Christopher Vinnard ◽  
Isabel Manley ◽  
Brittney Scott ◽  
Mariana Bernui ◽  
Joella Adams ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Pilot Study ◽  
Bacterial Translocation ◽  
Immune Activation ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Short Report ◽  
Hiv Viral Load ◽  
Time Curve ◽  
Immunodeficiency Virus

Background. Rifampin malabsorption is frequently observed in tuberculosis patients coinfected with human immunodeficiency virus (HIV) but cannot be predicted by patient factors such as CD4+ T cell count or HIV viral load. Methods. We sought to describe the relationship between HIV-associated immune activation, measures of gut absorptive capacity and permeability, and rifampin pharmacokinetic parameters in a pilot study of 6 HIV-infected, tuberculosis-uninfected patients who were naïve to antiretroviral therapy. Results. The median rifampin area under the concentration-versus-time curve during the 8-hour observation period was 42.8 mg·hr/L (range: 21.2 to 57.6), with a median peak concentration of 10.1 mg/L (range: 5.3 to 12.5). We observed delayed rifampin absorption, with a time to maximum concentration greater than 2 hours, in 2 of 6 participants. There was a trend towards increased plasma concentrations of sCD14, a marker of monocyte activation in response to bacterial translocation, among participants with delayed rifampin absorption compared to participants with rapid absorption (p=0.06). Conclusions. Delayed rifampin absorption may be associated with elevated markers of bacterial translocation among HIV-infected individuals naïve to antiretroviral therapy. This trial is registered with NCT01845298.

scholarly journals Comparison of Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Solithromycin (CEM-101) in Healthy Adult Subjects

2012 ◽  
Vol 56 (10) ◽  
pp. 5076-5081 ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
J. Gordon Still ◽  
Kay Clark ◽  
Prabhavathi Fernandes
Keyword(s):  
Steady State ◽  
High Performance ◽  
Healthy Adult ◽  
Plasma Concentrations ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Drug Concentrations ◽  
The Mean

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.

scholarly journals Population Pharmacokinetics of Tenofovir in Human Immunodeficiency Virus-Infected Patients Taking Highly Active Antiretroviral Therapy

2005 ◽  
Vol 49 (8) ◽  
pp. 3361-3366 ◽  
Author(s):  
Vincent Jullien ◽  
Jean-Marc Tréluyer ◽  
Elisabeth Rey ◽  
Patrick Jaffray ◽  
Anne Krivine ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Highly Active Antiretroviral Therapy ◽  
Plasma Clearance ◽  
Distribution Volume ◽  
Tubular Dysfunction ◽  
Concomitant Treatment ◽  
Time Curve ◽  
Mixed Effects Modeling ◽  
Highly Active ◽  
Immunodeficiency Virus

ABSTRACT The influence of renal function on tenofovir pharmacokinetics was investigated in 193 human immunodeficiency virus (HIV)-infected patients by the use of a population approach performed with the nonlinear mixed effects modeling program NONMEM. Tenofovir pharmacokinetics was well described by a two-compartment open model in which the absorption and the distribution rate constants are equal. Typical population estimates of apparent central distribution volume (Vc /F), peripheral distribution volume (Vp /F), intercompartmental clearance (Q/F), and plasma clearance (CL/F) were 534 liters, 1,530 liters, 144 liters/h and 90.9 liters/h, respectively. Apparent plasma clearance was related to body weight/serum creatinine ratio (BW/SCR) and to the existence of a tubular dysfunction. Concomitant treatment with lopinavir/ritonavir was found to decrease tenofovir clearance. Individual Bayesian estimates of CL/F were used to calculate the tenofovir area under the concentration-time curve from time zero to 24 h (AUC0-24). In patients without tubular dysfunction, AUC0-24 values markedly decreased from 6.7 to 1.4 mg · h/liter for BW/SCR increasing from 0.44 to 1.73. The relevance of a dosage adjustment based on BW/SCR should be further evaluated.

scholarly journals Pharmacokinetic Profile of μSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats

2015 ◽  
Vol 10 (9) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Rosario Russo ◽  
Angelo Mancinelli ◽  
Michele Ciccone ◽  
Fabio Terruzzi ◽  
Claudio Pisano ◽  
...  
Keyword(s):  
Oral Administration ◽  
Plasma Concentrations ◽  
Compartmental Analysis ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Sprague Dawley ◽  
Time Curve ◽  
Maximum Plasma Drug Concentration

Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (μSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t1/2), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with μSMIN Plus™ compared with animals treated with micronized diosmin. In particular, μSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for μSMIN Plus™, which may represent a new tool for CVI management.

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